Cerebral Cavernous Malformations (CCM) are leaky vascular lesions that cause hemorrhagic strokes, seizures, and neurological deficits. Familial CCM type 1 (fCCM1) is an autosomal dominant disease caused by mutations in the KRIT1 gene, and is typically characterized by multiple lesions on MRI that increase in number and size over time. Patients present with marked variability of disease burden, even among carriers of the same gene mutation, family or age. Currently only neurosurgical options are available to patients, although recent data from CCM animal models show promising benefits of drugs that target RhoA (statins and fasudil) for stabilizing endothelial junctions and reducing vascular leakage. In this project, we will leverage our considerable efforts over the past 5 years to recruit, phenotype, and identify modifiers of CCM disease severity in fCCM1 patients with the same founder mutation (Q455X), known as the Common Hispanic Mutation (CHM). Our long-term goal is to identify biomarkers for disease severity, which could aid in identifying patients at high risk for hemorrhage who would benefit most from pharmacologic therapy, and sets the stage for future clinical treatment trials. In the next funding period, we will continue longitudinal follow-up of 300 CCM1-CHM cases to ascertain outcomes and better understand the natural history of the disease, build on our existing genome wide association data to investigate the role of inflammation in CCM, and expand our focus on biomarker development for clinical trials, including gene expression and neuroimaging biomarkers. We will recruit a replication cohort of 300 fCCM1 cases caused by CHM and other CCM1 gene mutations to assess generalizability of findings in the CCM1-CHM cohort, and collect new data for follow-up studies (including plasma and serum samples, and surgically resected tissue specimens). We propose the following aims: Aim 1: To longitudinally characterize the phenotypic expression and natural history of CCM1-CHM patients. Aim 2: To investigate the role of inflammation in CCM1 disease progression. Aim 3: To develop biomarkers predictive of disease severity and progression for medical treatment of CCM.